We screened a panel of synthetic compounds for inhibition of HIV-1 infection of primary macrophages cultures. Three positive leads ITI-Ol I, ITI-053 and 111-062 were selected and shown to specifically interrupt the binding of isolated pre-integration complexes (PlC) with recombinant karyopherin alpha. In addition, the three compounds inhibited the nuclear importation of the PlC carrying the nascent cDNA as determined by reduction of 2-LTR circle forms of the viral DNA. ITI-011 and ITI-062 were also shown to inhibit infection of primary activated peripheral blood mononuclear cells (PBMC), as well as to abrogate infection of lymphoid tissue blocks in an in vitro histoculture model for HIV-I infection. ITI001 exhibited additive effect when combined with AZT or nelfinavir, and was active against an AZT resistant virus. Preliminary analysis showed that ITI-011 had an in vitro therapeutic index of more than 500 and did not alter primary CD4+ T cell activation at the effective antiviral concentrations. ITI-011 was orally bio-available in rodents, and exhibited little to no acute animal toxicity. Additional pre-clinical characterization of ITI-Ol1, as well as full characterization of ITI-053 and ITI-062 will be pursued in the Phase II SBIR sponsored studies, to determine the optimum lead candidate for initiation of Phase I clinical studies. PROPOSED COMMERCIAL APPLICATION: Not Available